The bioavailability corresponds to the active principle amount being administered reaching the systemic circulation. The efficiency of an active principle depends on the bioavailability thereof.
Many active principles suffer, through the oral route, from a low bioavailability.
Before reaching the vena cava, an active principle is conveyed through the gastrointestinal tract and passes through the intestine wall and the liver. At the liver level, the active principles may be metabolised in an inactive form and are subjected to the effect of the first hepatic passage before reaching the systemic circulation. Such an effect of the first hepatic passage is responsible for the low oral bioavailability of most of the active principles.
Another cause of the low bioavailability is the low solubility of the active principles, which are particularly little hydrosoluble. The absorption mode is then very long or incomplete leading to random therapeutic responses.
The low residence time in the gastrointestinal tract can also lead to a low bioavailability. If the active principle is not quickly dissolved or cannot penetrate into the epithelial membrane (this is the case of a highly ionized or polar active), the absorption time may be insufficient. In such a case, the bioavailability is variable and very low. Another cause for the low bioavailability is attributed to the competitive reactions of the absorption phenomenon, i.e. the complex formation, the hydrolysis by the gastric acid or the digestive enzymes, the conjugation in the intestine wall, the absorption of other active principles, the metabolism through luminal microflora.
For further information regarding the bioavailability, refer to Merck Manual of diagnostic and therapy, section 22, Clinical pharmacology; chapter 298.
The physicochemical properties of the active principles govern the absorption potential thereof, however the properties of the galenic form being implemented widely determine the bioavailability and/or the solubility of the active principle.
An object of the invention is therefore an impregnated powder for increasing the bioavailability and/or the solubility such as previously defined, and more particularly allowing to increase the absorption, the solubility and/or the protection of the active principle in order to facilitate the administration of liposoluble and/or hydrosoluble molecules (generally with a low bioavailability), easy and cheap to manufacture, in contrast to the lyophilization and spraying method generally used in the prior art for adsorbing fat bodies on a solid support.
An object of the invention is a powder for increasing the bioavailability and/or the solubility of at least one active principle comprising a solid inert support, in a particle form impregnated by a liquid medium comprising a hydrophobic phase and a hydrophilic phase, at least one surfactant and at least one active principle wherein said active principle is (are) dissolved in one of said hydrophilic or hydrophobic phases, and in the form of a suspension in the other one of said phases.
Another object of the present invention is to provide a method for producing an impregnated powder allowing to increase the bioavailability and/or the solubility and in particular allowing to increase the absorption, the solubility and/or the protection of the active principle in order to make easier the administration of liposoluble and/or hydrosoluble molecules (generally with a low bioavailability) and wherein the integrity of the active principles is maintained.
Still another object of the present invention is the use of an impregnated powder for increasing the bioavailability and/or the solubility such as previously defined, and more particularly allowing to increase the absorption, the solubility and/or the protection of the active principle in order to make easier the administration of liposoluble and/or hydrosoluble molecules (generally with a low bioavailability), for formulating various preparations.
The above-mentioned objects are reached according to the invention by an impregnated powder for increasing the bioavailability and/or the solubility of at least one active principle comprising a solid inert support, in a particle form impregnated by a liquid medium comprising a hydrophobic phase and optionally a hydrophilic phase, at least one surfactant and at least one active principle dissolved in at least one of said phases, wherein said active principle(s) is(are) also present in at least one of said phases in the form of a suspension.
It is meant herein under “suspension” a dispersion of solid particles in a liquid medium.
Preferably, one of the hydrophobic or hydrophilic phases is in a dispersed form in the other phase.
The liquid medium may moreover optionally comprise one or more co-surfactant(s), or any other builder necessary for preparation, such as a penetration builder, a mucoadhesive agent, a preservative, a dye, a flavouring agent, etc. or mixtures thereof.
Preferably, the phase in which the active principle(s) is(are) dissolved is a saturated solution.
The impregnated powder can be obtained with a method comprising the following steps:                obtaining a liquid medium comprising a hydrophobic phase, and optionally a hydrophilic phase, at least one surfactant and at least one active principle dissolved in at least one of said phases and present in at least one of said phases in the form of a suspension;        mixing a suitable amount of the liquid medium and a suitable amount of an inert solid support in a particle form liable to absorb the liquid medium; and recovering an impregnated powder.        
Preferably, the dissolved active principle and the active principle in the form of a suspension are located in distinct phases.
In a first embodiment, the liquid medium is obtained by solubilizing an amount of active principle(s) in one of said phases, mixing to the phase containing the active principle(s) dissolved the other one of said phases, adding an additional amount of active principle(s) to the two phase blend so as to form a suspension of the active principle(s).
In another embodiment, the liquid medium is obtained by mixing both phases and adding an amount of active principle(s) sufficient to obtain the dissolution of the active principle(s) in at least one of the phases and a suspension of the active principle(s) in at least one of the other phases.
The active principle(s) may be solubilized or dispersed in the hydrophobic phase or in the hydrophilic phase or in both.
The combination of all these components allows to increase the bioavailability and/or the solubility of the active principle(s).
The method for producing the impregnated powder increasing the bioavailability and/or solubility has the advantage of being easy and cheap to be implemented. All the liquid and powder stirring methods known to the man skilled in the art are useable.
An important feature of the impregnated powder according to the invention is the bioavailability and/or solubility increase of the active principle(s) contained therein.
The impregnated powder for increasing the bioavailability and/or solubility according to the invention may be used as such or included in various formulations.
Thus, another feature of the impregnated powder for increasing the bioavailability and/or solubility according to the invention is to enable the production of various galenical forms, more particularly, deliverable through oral route or mucosal route (oral, nasal, vaginal) or through cutaneous route with a view to a local or systemic action. The galenical forms are generally dry forms such as bare or blistered tablets, sugar-coated tablets, coated tablets (soluble coating, pH-dependent or independent coating, with a gastric, intestinal or other release), matricial tablets, osmotic tablets, multilayered tablets, effervescent tablets, dual core tablets, floating tablets, forms with gastric residence and/or floating forms, mucoadhesive forms, capsules, powders, multiparticle forms such as granules, coated or non coated microgranules (sugar-coated, with a soluble pH-dependent coating), mucoadhesive forms, atomised solids. Such an impregnated powder may also be applied onto fabric-type supports (wipes) to be applied on the body surface, etc.
The resulting galenical forms may have any packaging form.
The impregnated powder for increasing the bioavailability and/or solubility according to the invention has also the advantage of allowing high active material contents. A liquid medium may thus be obtained, saturated or not and dispersed with active material. The so-obtained liquid medium may be impregnated on an inert support.
The hydrophobic phase of the impregnated powder for increasing the bioavailability and/or solubility may be made of any non toxic compounds conventionally used for forming an oil phase.
In particular, the hydrophobic phase may be selected from vegetable, animal, mineral or synthetic or semi-synthetic oils, mono-, di- or triglycerides, fatty alcohols and any derivatives thereof, polyol esters, liquid paraffin, long chain hydrocarbons such as squalane and squalene, tocopherol and the derivatives thereof, aliphatic fatty acids, fatty acid esters, silicone oils, phospholipid compounds and the derivatives thereof, and mixtures thereof.
The oils making up the oil phase may be polar or apolar oils.
Vegetable oils may include sunflower, olive, soja, corn, sesame, sweet almond, peanut, rapeseed refined oils, as well as avocado, wheatgerm, castor, coconut oils, etc . . . .
Animal oils may include cod-liver oil, shark-liver oil and lanolin oil.
Mineral oils may include paraffin oil.
Fatty alcohols may include behenyl alcohol, cetyl alcohol, isocetyl alcohol, isostearyl alcohol, lauryl alcohol, 2-octyl-dodecanol, oleyl alcohol, meristyl alcohol and stearyl alcohol.
Aliphatic fatty acids may include isostearic acid, lauric acid, linoleic acid, oleic acid.
Fatty esters may include dibutyl adipate, dibutyl sebacate, dicetyl adipate, diethyl sebacate, dihexyl adipate, diisocetyl adipate, diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate, diisostearyl adipate, dioctyl adipate, dioctyl sebacate and dioctyl succinate, branched chain fatty esters such as 2-ethylhexyl isononanoate, 2-ethylhexyl myristate, 2-ethylhexyl oxystearate, 2-ethylhexyl palmitate, 2-ethylhexyl pelargonate, 2-ethylhexyl stearate, isocetyl isodecanoate, isocetyl palmitate, isodecyl isononanoate, isononyl isononanoate, isopropyl isostearate, isopropyl laurate, isopropyl linoleate, isopropyl myristate, isopropyl oleate, isopropyl palmitate, isopropyl stearate, isostearyl isostearate, isostearyl lactate, isostearyl neopentanoate, isostearyl palmitate, isopridecyl isononanoate and tocopheryl linoleate, tribasic acid esters such as triisocetyl citrate, triisopropyl trilinoleate, triisostearyl trilinoleate, trilauryl citrate and trioctyl citrate, straight chain fatty esters such as lauryl lactate, lauryl myristate, lauryl palmitate, lauryl stearate, meristyl lactate, myristyl meristate, myristyl neopentanoate, myristyl propionate, myristyl propionate, myristyl stearate, oleyl erucate, oleyl linoleate, oleyl myristate, oleyl oleate, oleyl stearate, stearyl lactate and stearyl oleate.
Triglycerides may include caprylic/capric triglycerides, triisononanoin, triisostearin, trilaurin, trilinolein and triolein.
Silicone oils may include polyorganosiloxane oils, more particularly, polydimethylsiloxane oils, being volatile or non volatile, such as cyclic polydimethylsiloxane oils, having 3 to 6 silicon atoms, for example, cyclomethicone, as well as linear polydimethylsiloxanes.
Generally, the hydrophobic phase is 0.1% to 99.9% by weight, preferably, 5% to 60%, based on the total weight of the liquid medium containing the active principle(s).
The hydrophilic phase of the impregnated powder for increasing the bioavailability and/or solubility may be any aqueous non toxic phase conventionally used by the man skilled in the art.
Thus, the hydrophilic phase may consist in water (distilled or deionised), a hydroalcoholic mixture, in particular a water/alkanol mixture, such as ethanol, a buffered aqueous solution, a saline aqueous solution, a glucosed aqueous solution, and a water-polyethylene glycol, water-propylene glycol and water-glycerol mixture.
Generally, the aqueous phase is 0.1% to 99.9% by weight, preferably 5% to 60% based on the total weight of the liquid medium containing the active principle(s).
As previously indicated, the liquid medium comprising the active principle(s) comprises at least one non toxic surfactant. The surfactant may be non ionic, anionic, cationic or amphiphilic. Such a liquid medium may optionally be neutral or negatively charged, depending on the required functionalities.
(i) Non Ionic Surfactant(s)
The non ionic surfactants are also well known compounds per se (see more particularly “Handbook of Surfactants” by M. R. PORTER, Editions Blackie & Son (Glasgow and London), 1991, pages 116 to 178) and their nature does not show, in the scope of the present invention, any critical feature. Thus, they can be more particularly selected amongst (non limitative list) alcohols, alpha-diols, alkylphenols or polyethoxylated, polypropoxylated or polyglycerolated fatty acids, with one fatty chain comprising for example from 8 to 18 carbon atoms, the propylene oxide or ethylene oxide group number possibly ranging from 2 to 50 and the glycerol group number possibly ranging from 2 to 30. One can also mention the ethylene and propylene oxide copolymers, the ethylene and propylene oxide condensates on fatty alcohols; the polyethoxylated fatty amides preferably having from 2 to 30 ethylene oxide moles, the polyglycerolated fatty amides comprising on average from 1 to 5 glycerol groups and more particularly 1.5 to 4; the oxyethylenated sorbitan fatty acid esters having from 2 to 30 ethylene oxide moles; the saccharose fatty acid esters, the polyethyleneglycol fatty acid esters, the alkylpolyglycosides, the N-alkyl glucamine derivatives, the amine oxides such as the oxides of (C10-C14) alkyl amines or the N-acylaminopropylmorpholine oxides.
Non ionic surfactants comprise polyoxyethylenated fatty acid esters, saccharose esters, saccharoglycerides, lauryl ethers and derivatives polysorbate, sorbitan ester, dioctylsodium sulfosuccinate, bis-2-ethylhexyl sodium sulfosuccinate and derivatives, all sorbitan derivatives, polyoxyethylene glycol alkyl ether.
(ii) Anionic Surfactant(s)
Their nature does not show, in the scope of the present invention, any really critical feature.
Thus, as an example of useable anionic surfactants, alone or in mixtures, in the scope of the present invention, one may mention amongst others (non limitative list) salts (more particularly alkaline salts, including sodium salts, ammonium salts, amine salts, aminoalcohol salts or alkaline earth (magnesium) salts of the following compounds: alkylsulfates, alkyl-ethersulfates, alkylamidoethersulfates, alkylarylpolyethersulfates, sulphate monoglycerides; alkylsulfonates, alkylphosphates, alkylamido-sulfonates, alkylarylsulfonates, α-olefin-sulfonates, paraffin-sulfonates; alkyl-sulfosuccinates, alkylethersulfosuccinates, alkylamidosulfosuccinates; alkylsulfosuccinamates; alkylsulfoacetates; alkyletherphosphates; acyl-sarcosinates; acylisethionates and N-acyltaurates, the alkyl or acyl moiety of all these various compounds preferably comprising from 12 to 20 carbon atoms, and the aryl moiety preferably representing a phenyl or benzyl group. Anionic surfactants still useable may also include fatty acid salts such as the salts of oleic, ricinoleic, palmitic, stearic acids, coco oil acids or hydrogenated coco oil acids; acyl-lactylates with an acyl moiety comprising from 8 to 20 carbon atoms. One can also use low anionic surfactants, such as the uronic galactoside D alkyl acids, and the salts thereof, as well as the polyoxyalkylated carboxylic ether (C6-C24) alkyl acids, the polyoxyalkylated carboxylic ether aryl (C6-C24) alkyl acids, the polyoxyalkylated carboxylic ether amido (C6-C24) alkyl acids and the salts thereof, in particular those comprising from 2 to 50 ethylene oxide groups and the mixtures thereof.
Anionic surfactants comprise also petroleum sulfonate, sulfonated glycerides, alpha sulfonate and soaps.
Amongst the anionic surfactants, alkylsulfate salts (for example sodium alkyl sulfate) and alkylethersulfates and the mixtures thereof are preferably used according to the invention.
(iii) Amphoteric Surfactant(s)
The amphoteric surfactants, the nature of which does not show any critical feature in the scope of the present invention, can be more particularly (non limitative list) aliphatic secondary or tertiary amine derivatives, wherein the aliphatic moiety is a linear or branched chain comprising from 8 to 22 carbon atoms and containing at least one hydrosolubilizing anionic group (for example carboxylate, sulfonate, sulfate, phosphate or phosphonate), one can also mention (C8-C20)alkyl betaines, sulfobetaines, (C1-C6)alkylamidoalkyl (C8-C20)betaines or (C1-C6)alkylamidoalkyl (C8-C20)sulfobetaines.
Amphoteric surfactants comprise also synthetic, semi synthetic, natural modified, natural phospholipides with grafts (licithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phytoglycolipide, lysophosphatide, sphyngomyeline), alkylaminocarboxylic acids.
(iv) Cationic Surfactant(s)
The cationic surfactants, the nature of which does not show any critical feature in the scope of the present invention, can be more particularly (non limitative list) alkylated quaternary ammonium, alkylamine salts and amine oxides.
Cationic surfactants comprise cetrimide, primary amines, fatty amine acetate and chlorhydrate, quaternary ammonium salts, substituted diamine amides and derivatives, diethylene triamine amides.
Generally, the amount of surfactant present is of at least 1% by weight based on the total weight of the liquid medium, generally from 2% to 70% by weight and preferably from 10% to 60% by weight.
Preferably, the liquid medium also contains at least one co-surfactant. The co-surfactant is a compound with its molecule generally considerably smaller than that of the surfactant and the role thereof is to act on the molecular stack at the droplet interface, such that the liquid medium formation is energetically favoured.
Preferred co-surfactants may include (non limitative list) alkanols, more particularly C3 to C6 alkanols, glycol ethers, glycol and the derivatives thereof, propylene glycol and the derivatives thereof, lauric esters of propylene glycol, polyglycerol and the derivatives thereof, oleic esters of polyglycerol and ethyldiglycol.
Co-surfactants comprise polyoxylated castor oil, hydrogenated polyoxylated castor oil, polyglyceryl and derivatives, organic acids (oleic acid, naphtalenic acid, resin acid, diacid-alcohols (tartric acid . . . ) triacid-alcohols (citric acid), diacids (malonic acid, maleic acid, succinic acid, adipic acid), hydrophile and/or lipophile alcohols (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, isoamylic alcohol, hexanol, heptanol, octanol . . . ) hydrophile and/or hydrophobe glycols (ethylene glycol, propylene glycol, isopropylene glycol, butylene glycol, 2-3 butanediol, isobutene glycol, 2-4 butanediol, hexylene glycol . . . ) fatty acids and the derivatives thereof (lauric acid, palmitic acid, oleic acid, stearic acid), polyols (glycerol, trimethylolpropane, 2-3-4-pentanetriol) amines and polyamines and the derivatives thereof (dimethylamine, ethylene diamine, diethylene triamine, triethylene tetramine, tetra ethylene pentamine . . . ), amino-alcohols (ethanolamine, diethanolamine, triethanolamine, diethyl amino ethanol . . . ).
The co-surfactant, when used, generally is 0.01% to 60% by weight based on the total weight of the liquid medium containing at least one active principle.
The active material(s) included in the liquid medium may be any active principle with an activity in the pharmaceutical, parapharmaceutical and cosmetic field, in the field of food complements or in the food processing industry, in particular in the cosmetic and/or therapeutic fields, preferably the therapeutic one. Such active principles may be soluble and/or dispersible in one or the other of the liquid medium components. In particular, the active principles can be hydrosoluble, liposoluble or amphiphilic.
The active principles from chemical, natural or biological origin, used according to the invention may be selected amongst those conventionally used in the following pharmacotherapeutic families: allergology, anesthesia/resuscitation, cancerology and hematology, cardiology and angiology, contraception and pregnancy interruption, dermatology, endocrinology, gastro-entero-hepathology, gynecology and obstetrics, immunology and transplantation drugs, infectiology and parasitology, diabetes metabolism and nutrition, neurology/psychiatry, ophthalmology, otorhinolaryngology, pneumology, rhumatology, stomatology, toxicology, urology/nephrology, as well as amongst analgesics/antipyretics and antispasmodics, anti-inflammatory drugs, contrast products used in radiology, haemostatics and blood treatment products and derivatives.
Advantageously, the active principles may be selected amongst the group comprising active principles passing the mucosal barrier and reaching the systemic circulation, such as cyproterone acetate, Δ-4-androstenedione, 3-keto-desogestrel, desogestrel, gestodene, estradiol and the derivatives thereof, norethisterone acetate, progesterone, testosterone, dihydro-testosterone, trinitrine, fentanyl, nitroglycerin, nicotine (S(−) nicotine), scopolamine, clonidine, isosorbide dinitrate, levonorgestrel in combination with ethinylestradiol or with estradiol, androstanolone, alclometasone dipropionate, phlorglucinol, molsidomin, as well as their combinations.
They may also be selected amongst the active principles passing the mucosal barrier and having a localized action such as: acetazolamide, acyclovir, adapalene, alclomethasone dipropionate, amcinonide, ameleine, bamethan sulphate+escin, betamethasone valerate, betamethasone dipropionate, bufexamac, cafein, calcipotriol monohydrate, cetrimonium bromide, clobetasol propionate, crilanomer, desonide, dexpanthenol, diclofenac, diflucortonole valerate, difluprednate, diphenydramine hydrochloride, econazole nitrate, erythromicin, flumetasone pivalate, fluocinolone acetonide, fluocinodin, fluocortolone, fluocortolone hexanoate, fluocortolone pivalate, hydrocortisone, hydrocortisone acetate, ibacitabin, ibuprofen, imiquimod, ketoconazole, ketoprofen, lidocaine, metronidazole, miconazole nitrate, minoxidil, acidic niflumide, penciclovir, benzoyl peroxide, piroxam, iodized povidone, promestriene, pyrazonibutasone, roxithromycin, sulfacetalmide, triamsinolone, tazarotene, tretinoin and isotretinoin, triclocarban, vidarabin monophosphate, as well as their combinations.
They may also be selected amongst the following active principles: adrenergic β-3 agonist, growth hormone, oxibutinin, buprenorphin, pergolid, nestoron, 7 α-methyl-19-nortesterone, mecamylamin, salbutamol, selegilin, buspirone, ketotifen, lidocain, ketorolac; eptazocin, insulin, α-interferon, prostaglandins, 5-aminolevulinic acid, benzodiazepine alprozolam, diclofenac, fenoprofen, flubiprofen, ketoprofen, methylphenidate, miconazole, piroxicam, buprenorphin, alprozolam, dexmedetomidin, prazosin (α-adrenergic antagonist), alprostadil, tulobuterol (β-adrenergic agonist), thinylestradiol+norelgestromin, ketorolac, physostigmin, medindolol (β-adrenergic agonist), rotigotin, (D2 dopamin antagonist), thiatolserin as well as their combinations.
They may also be selected amongst the following active principles Esomeprazole, Melagatran (in case of thrombosis), Rosuvastatine, Ezetimide, Pitavastatine (hyperlipidemia), Mitiglinide (type II diabetes), Cilomilast, Viozan (asthma), Aripipazole (psychiatry), Omapatrilat (hypertensor), Orzel (cancerology), Capspofongine acetate, Voriconazole (infections), new COX inhibitors such as Etoricoxib (inflammation), Valdecoxib (arthritis) and Parecoxib, P-antagonist substance (depression), Darifenacin (urology), Eletriptan (migrain), Alosetron, Tegaserod, Capravirin (HIV) as well as their combinations.
Preferred active principles according to the invention may include vitamin A derivatives (for example isotretinoin, coenzyme Q10), antiviral agents (for example acyclovir), analgesics (for example indometacin, naproxene), anti-ulcer agents (for example omeprazole, lansoprazole), antimoulds (for example Cyclosporin), antibiotics (cefaclor, amoxicillin, cloxacilin), sex hormones (antiestrogenes, for example raloxifene; estrogenes, for example estradiol, estradiol hexahydrobenzoate, estradiol undecylate, estradiol valerate, estradiol ethinyl; progestins, for example norethisterone enanthate, progesterone; androgens, for example testosterone propionate, testoterone cyclohexylmethylcarbonate, and antiandrogens, for example cyproterone acetate.
The active principles may be also selected amongst those conventionally used in cosmetics, parapharmacy and for food complements. Such active principle contents are those conventionally used in the mentioned fields.
Cosmetic and parapharmaceutical active principles may include emollients, wetting agents, pigments and dyes, anti-wrinkle agents (retinol), anti-fungal agents, anti-acne agents, softening agents, perfumes and vitamins.
Actives for food complements may include vitamins (A, B, E, C, B1, B2, B3, B6, B9, B12, B8H, B5, . . . ), minerals (calcium, phosphorus, iron, magnesium, zinc, iodine, . . . ), carotenoids (alpha-caroten, beta-caroten, gamma-caroten, lutein, zeaxanthin, cryptoxanthin, lycopene, . . . ), phyto-estrogens, isoflavones (genistein, diadzein, biochanin A, formononetin, . . . ), lignans (enterolactone, enterodiol, . . . ), coumestanes (coumestrol), vegetable extracts (fennel, heather, blackcurrant, grape seed extracts, fucus, ginseng, green coffee, ginger, . . . ), oils (oenothera, wheatgerm, borage, marrow seeds, . . . ), clays (diosmestite-montmorillonites, . . . ), ferments and yeasts, as well as apple pectin.
Depending on the selected active principle (or the active principle mixture), several liquid medium formulations are available depending on the desired release profile.
Generally, the active material content of the impregnated powder for increasing the bioavailability and/or the solubility according to the invention ranges from 0.001% to 70% by weight, preferably 0.5% to 60% by weight, based on the liquid medium total weight, depending on the active material nature.
The liquid medium may also contain a penetration builder or a mixture of builders intended to improve the passage of the active molecules through the involved membrane. Penetration builders may include those which may be selected in the group consisting of aliphatic fatty acid esters such as the isopropyl myristate, fatty acids such as oleic acid; alcohols or polyols such as ethanol, propylene glycol and polyethylene glycol; essential oil and terpene derivatives components (such as eugenol, geraniol, nerol, eucalyptol, menthol); preferably non ionic surfactants, such as polyoxyethylene sorbitan (fatty acid ester), polyoxyethylene alkyl ether, polyoxyethylene derived from castor oil, as well as their mixtures; hydrating agents such as glycerin, urea; keratolytic agents such as alphahydroxyacids, 23-lauryl ether, aprotinin, nitrogen, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrins, dextran sulfate, lauric acid, lysophosphadidylcholine, methoxysalicylate, methyloleate, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salycilate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides and alkyl glycosides.
The liquid medium may also comprise an adhesive agent (mucous membrane, skin) so as to obtain finally an impregnated powder increasing the bioavailability and/or the bioadhesive solubility. Adhesive agents may include carbomers, polyoxyethylenes, methylcelluloses, carboxymethyl-celluloses, sodium carboxymethylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses, polyvinyl-pyrrolidone, polyvinyl alcohol, polyisobutylene, polyisoprene, xanthane gum, locust bean gum, chitosan, polycarboxylates, acrylic/methacrylic acid copolymers, acrylic acid/acrylamide copolymers, acrylic acid/methylmethacrylate copolymers, acrylic acid/polyethylene glycol copolymers, polyacrylic acid/butyl acrylate copolymers, 2-hydroxy-ethylmethacrylate (HEMA), the compound commercialized under the trademark CYDOT® by 3M corporation (carbopol associated with polyisobutylene), (low viscosity) pectin, methylvinylether/maleic anhydride copolymers, tragacanth, monoethylether, monomethylether, waxy corn starch, sodium stearyl fumarate, sodium hyaluronate, guar gum, sodium alginate, starch, dextran and the derivatives thereof, acrylic polymers, silicones and siliconed derivatives, colophan resins and the mixtures thereof.
Generally, the amount of adhesive agents present in the liquid medium is 0.01% to 70% by weight based on the total weight of the liquid medium.
It may also be interesting to introduce into the liquid medium one or more thermoreversible polymers such as the compounds available under the trademarks LUTROL® and XULOGLUCAN®, in particular for administration through mucosal or cutaneous route. Thus, the impregnated powder according to the invention may be gelled by contact with the mucous membrane or the epiderm. Generally, such polymers are present in an amount ranging from 0.01% to 70% by weight based on the total weight of the liquid medium.
The invention has also the advantage to allow for high active principle contents.
The liquid medium is generally 1% to 99%, preferably 20% to 90%, more preferably 40% to 90%, and more preferably 50% to 80%, based on the total weight of the impregnated powder increasing the bioavailability and/or the solubility.
The inert support in a particle form may be any non toxic support, chemically inert relative to the liquid medium containing the active principle and to its constituents, suitable for the contemplated application and able to be impregnated by the liquid medium without damaging the integrity thereof.
These are generally non toxic inert powders having a strong adsorbing power, liable to adsorb several times their own weight in liquid.
The suitable particle inert supports may include natural silicas, silica gels, fumed silicas, precipitated silicas, clays, talc, magnesium hydroxide, aluminum hydroxide, magnesium oxide, maltodextrins, cyclodextrins, some cellulose derivatives such as cellulose powder and the mixtures thereof.
The preferred particle inert supports are the silicas. The silicas may be hydrophilic, hydrophobic or amphiphilic. Suitable silicas are available under the trademarks AEROSIL® (hydrophilic, hydrophobic), AEROPERL® (hydrophilic, hydrophobic), SYLOID® and SIPERNAT® (amphiphilic).
Amongst the clays, one can mention montmorillonites and bentonites.
Maltodextrins are available under the trademark LYCATAB®.
The particle mean size of particle inert supports according to the invention generally ranges from 0.001 to 300 μm, preferably from 1 to 100 μm.
Generally, the particle inert support is 1% to 90%, preferably 10% to 80%, more preferably 10% to 60%, most preferably 20% to 50% by weight based on the total weight of the impregnated powder increasing the bioavailability and/or the solubility.
The impregnated powder may generally comprise any other builder necessary for the preparation such as (non limitative list) flavoring agents, perfumes, essential oils, dyes, antioxidants, preservatives, sweeteners, fillers, etc. or the mixture thereof.
Generally, the particle size of the impregnated powder for increasing the bioavailability and/or the solubility according to the invention ranges from 1 to 100 μm, preferably from 20 to 50 μm.
The impregnated powder for increasing the bioavailability and/or the solubility according to the invention may easily be produced through the following general mode: first a liquid medium is produced, containing at least one active principle in a form both dissolved and in the form of a suspension. The liquid medium containing at least one active principle is progressively impregnated under stirring on the particle inert support. After homogenization of the mixture, the formulation is recovered in the form of an impregnated powder for increasing the bioavailability and/or the solubility.
FIGS. 1 to 4 show block diagrams of the main steps of alternative production methods for the impregnated powder for increasing the bioavailability and/or the solubility according to the invention.
Referring to FIG. 1, it is shown the main production steps of an impregnated powder for increasing the bioavailability and/or the solubility according to the invention comprising a hydrophobic active principle.
As shown in FIG. 1, first all the components with a lipophilic nature are mixed (the hydrophobic medium, the surfactants and optionally the co-surfactant), followed by a solubilization of the hydrophobic active principle, under stirring, in this hydrophobic medium. In order to have the maximum thermodynamic activity, the active principle is solubilized up to saturation, but the case where it is not up to saturation can be contemplated.
After solubilization of the hydrophobic active principle, the aqueous medium is introduced under stirring. A liquid is obtained containing the active principle(s) up to saturation or not depending on the case. At this stage, an additional amount of the hydrophobic active principle is added, under stirring, until the desired active principle content is obtained. A suspension is thereby obtained, generally in a creamy and opaque semi-solid form.
Such a suspension is then impregnated on the inert solid support under simple stirring. The impregnated powder for increasing the bioavailability is thereby obtained.
FIG. 2 relates to an alternative of the method in FIG. 1 which differs from the latter in that the hydrophilic medium is first added under stirring to the hydrophobic medium, followed by the addition, under stirring, of the desired amount of hydrophobic active principle until the suspension is obtained. The desired active principle amount can thus be obtained. As in the previous case, the suspension is then impregnated on the inert support with a simple stirring.
The methods in FIGS. 3 and 4 are similar to those in FIGS. 1 and 2 respectively, but relate to the incorporation of a hydrophilic active principle, and for which the preparation and incorporation order of hydrophobic medium and the aqueous medium has been inverted.
As previously indicated, the impregnated powder for increasing the bioavailability and/or the solubility according to the invention may be used for preparing various forms, in particular galenical forms to be administrated through oral or mucosal route, as well as forms used in cosmetic industry, food complements, food processing industry and parapharmaceutical industry.
In the case of an amphiphilic active principle, the making method remains similar to those previously described.
The impregnated powder for increasing the bioavailability and/or the solubility may also be used alone as such and in various forms in (non limitative list of the invention) bags, stick-packs, pressurized or non pressurized flasks with or without applicators, wipes, etc.
According to the composition of the liquid medium, the impregnation support selected amongst inert powders, the selected galenical form, various release profiles are then available such as an immediate, modified, delayed, bimodal, pulsed release.
The impregnated powder for increasing the bioavailability of the invention may also be converted into capsules, stick packs (and remain in a powder form), bags, powder sprays for nasal, oral or vaginal route, powder sprays with special applicators, etc.
In order to obtain a tablet, it is just sufficient to add one or more diluents (for example, microcrystalline cellulose, lactose, cellulose powder, dicalcium phosphate, sucrose, starch, bicarbonate, mannitol, . . . ), lubricants (for example magnesium stearate, sodium stearyl fumarate, . . . ), binders (for example polyvinylpyrrolidone-vinyl acetate copolymer, povidone, . . . ), disintegration agents (starch and derivatives, sodium starch glycolate, alginate, microcrystalline cellulose, sodium croscarmellose, crosspovidone, . . . ) or others excipients needed for producing tablets.
The tablets may be obtained through direct compression, wet route granulation, dry route granulation or any other techniques known to the man skilled in the art.
It is possible to make multilayered or dual-core tablets, coated tablets (enteric coatings, taste-concealing coating), effervescent tablets, gastric residence or floating tablets.